Several years of design, synthetic effort, and screening of oleanolic acid (1) derivatives led to the discovery of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 2) and its methyl ester, bardoxolone methyl (3) (Sporn, et al. (2011) J. Nat. Prod. 74:537; Honda, et al. (1998) Med. Chem. Lett. 8:2711), as lead compounds for further development and eventual clinical trials. Following the initial discovery of CDDO as a potent multifunctional molecule (Honda, et al. (2000) J. Med. Chem. 43:1866), lead compounds with enhanced activity and reduced toxicity have been identified. For example, methylation and amidation of the C-28 carboxylic acid moiety afforded CDDO-methyl ester (bardoxolone methyl) and CDDO-ethyl amide 4, respectively.

Synthetic triterpenoids (TP) are active at low nanomolar concentrations and inhibit the induction of iNOS (inducible nitric oxide synthase) in primary macrophages or in RAW264.7 macrophage-like cells stimulated with inflammatory cytokines. CDDO-Me (3), with significantly higher activity than that of CDDO, has advanced to clinical trials for a variety of antiinflammation disorders, including cancer and diabetic neuropathy (Liby & Sporn (2012) Pharmacol. Rev. 64:972). Similarly, other CDDO derivatives are known to possess antitumor activities (Tran, et al. (2008) J. Neuroinflammation 5:14; Liby, et al. (2010) Cancer Prev. Res. 3:1427; Townson, et al. (2011) Clin. Exp. Metastasis 28:309; Kim, et al. (2012) Cancer Prev. Res. 5:89; Tran, et al. (2012) Cancer Prev. Res. 5:726; Kress, et al. (2007) PLoS One 2:e559).
Oleanolic acid amino acid conjugates have been synthesized as potent inhibitors of osteoclast formation (Zhang, et al. (2005) Bioorg. Med. Chem. Lett. 15:1629). Furthermore, amino acid conjugates of betulinic acid exhibit potent activity against melanoma (Jeong, et al. (1999) Bioorg. Med. Chem. Lett. 9:1201) and HIV (Dang, et al. (2012) Bioorg. Med. Chem. Lett. 22:5190). The anti-HIV activity of triterpenoid maslinic acid is also enhanced by its conjugation to amino acids (Parra, et al. (2009) Bioorg. Med. Chem. 17:1139).